17-76376994-C-T

Position:

• chr17-76376994-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000545180.5(SPHK1):​c.-658+182C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 152,126 control chromosomes in the GnomAD database, including 4,095 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (4095 hom., cov: 32)
• Consequence: SPHK1 ENST00000545180.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.56

Genes affected

PRPSAP1 (HGNC:9466): (phosphoribosyl pyrophosphate synthetase associated protein 1) Enables identical protein binding activity. Predicted to be involved in 5-phosphoribose 1-diphosphate biosynthetic process and purine nucleotide biosynthetic process. Predicted to be part of ribose phosphate diphosphokinase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SPHK1 (HGNC:11240): (sphingosine kinase 1) The protein encoded by this gene catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (S1P), a lipid mediator with both intra- and extracellular functions. Intracellularly, S1P regulates proliferation and survival, and extracellularly, it is a ligand for cell surface G protein-coupled receptors. This protein, and its product S1P, play a key role in TNF-alpha signaling and the NF-kappa-B activation pathway important in inflammatory, antiapoptotic, and immune processes. Phosphorylation of this protein alters its catalytic activity and promotes its translocation to the plasma membrane. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPSAP1	ENST00000423915.1	c.-140+7387G>A		intron_variant		4
PRPSAP1	ENST00000442767.1	c.44+6852G>A		intron_variant		5
SPHK1	ENST00000545180.5	c.-658+182C>T		intron_variant		2		P2
SPHK1	ENST00000591651.5	c.-296+182C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29380 AN: 152008 Hom.: 4083 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.193

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.194 AC: 29444 AN: 152126 Hom.: 4095 Cov.: 32 AF XY: 0.191 AC XY: 14214 AN XY: 74376

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0471

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.139

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.194

Alfa AF: 0.172 Hom.: 665

Bravo AF: 0.202

Asia WGS AF: 0.112 AC: 387 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.41
DANN	Benign	0.37

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9892909; hg19: chr17-74373075; COSMIC: COSV71121806; COSMIC: COSV71121806;